Influence of Chronic Oral Infections on Senescence and Vascular Degeneration

慢性口腔炎症疾病如牙周炎已被证明与不良心血管结果有关。这种相关性的潜在机制在很大程度上是未知的。衰老是指在哺乳动物细胞培养中描述的一种永久性不可逆生长停滞的表型，一些证据表明衰老在体内衰老过程中起着重要作用。高龄与牙周健康状况差以及牙周炎患病率和严重程度的增加有关，这一事实使我们假设(1)牙周炎通过全身可检测到的内皮细胞微炎症诱导局部牙龈上皮细胞衰老。后者是内皮功能障碍的发病机制和最终血管结构改变的相关环节，(2)预先存在的衰老不仅会导致对局部感染的更高易感性，而且还会导致更多牙周炎引起的血管功能改变，(3)作为概念的证明，干预衰老的策略，如内皮细胞中p16INKa的特异性知识，通过增加再生潜能来防止牙周炎引起的变化。我们将研究口腔细菌或细菌挑战细胞在体外诱导衰老，使用牙龈上皮细胞和脐内皮细胞。为了进一步探讨牙周炎诱导的衰老对心血管变化的直接影响，即动脉粥样硬化的发展，我们将进行体内研究。为此，将在自发形成动脉粥样硬化斑块的载脂蛋白E敲除小鼠（ApoE KO小鼠）中诱导实验性牙周炎。将P. gingivalis治疗的ApoE KO小鼠与未治疗的对照组进行比较，以证明牙周炎加速衰老并导致更大的心血管变化。年轻和年老小鼠的比较将阐明，是否预先存在的衰老导致对牙周炎引起的血管变化的更高易感性。然后，我们将使用内皮细胞中p16INKa特异性敲低的ApoE KO小鼠来测试这些小鼠是否免受P. gingivali治疗的ApoE KO小鼠血管变化的影响。这些后期的研究将证明这样一个概念，即干扰衰老会导致再生潜力的增加，从而有助于抵消慢性炎症过程引起的血管变化。除了对牙周炎过程的重要性外，该项目还具有进一步的意义，通过诱导衰老变化，为慢性炎症过程和血管变性之间的因果关系提供了证据。

Chronic oral inflammatory diseases like periodontitis have been shown to be linked to adverse cardiovascular outcomes. The underlying mechanism of this correlation is largely unknown. Senescence refers to a phenotype of permanent irreversible growth arrest described in mammalian cells in culture, and several lines of evidence point towards an important role of senescence in aging processes in vivo. The fact that advanced age is associated with poor periodontal health and an increased prevalence and severity of periodontitis leads us to hypothesize (1) that periodontitis induce cellular senescence locally in gingival epithelial cells and via the systemically detectable microinflammation in endothelial cells. The later is the relevant link for the pathogenesis of endothelial dysfunction and eventually structural vascular changes, (2) that preexisting senescence will not only lead to a higher susceptibility towards local infections, but also to more periodontitis-induced changes in vascular function, and (3) that , as a proof of concept, interventional strategies interfering with senescence, like the specific knowdown of p16INKa in endothelial cells, will lead to protection from those periodontitis-induced changes by increasing the regenerative potential. We will study the induction of senescence by oral bacteria or bacterial-challenged cells in vitro using gingival epithelial and umbilical endothelial cells to. To further explore the direct impact of periodontitis-induced senescence for the induction of cardiovascular changes, i.e. the development of atherosclerosis, we will perform in vivo studies. For this purpose, experimental periodontitis will be induced in Apolipoprotein E knockout mice (ApoE KO mice) that spontaneously develop atherosclerotic plaques. P. gingivalis-treated ApoE KO mice will be compared with untreated controls to prove that periodontitis accelerates senescence and leads to greater cardiovascular changes. The comparison of young and old mice will clarify, whether preexisting senescence leads to higher susceptibility towards periodontitis-induced vascular changes. We will then use ApoE KO mice with a specific p16INKa knockdown in endothelial cells to test whether these mice are protected from the vascular changes seen in P. gingivalis-treated ApoE KO mice. These later studies will be the proof of concept that interfering with senescence leads to an increased regenerative potential that in turn helps to counteract the vascular changes caused by a chronic inflammatory process. Apart from its importance for the process of periodontitis, this project has further implications by providing evidence for a causal relationship between chronic inflammatory processes and vascular degeneration through the induction of senescent changes.